Intestinal lymphatic uptake has long been proposed as a route for drugs to increase systemic bioavailability by avoiding first pass metabolism and hepobiliary elimination pathways following oral administration. However, no strong data in the literature exists which suggest there is an oral delivery system which actually can target this absorption pathway to any great extent. Formulation of drugs in oils and fatty acids is a traditional approach which has shown some success, but is by no means predictable. These approaches have focused on compounds with high log P and high lipid solubility, and even under these conditions results have been mixed. This approach suffers from the limitation that most compounds have limited solubility in digestible oils or fatty acids to the extent that development into a solid dosage form is not practical, that is, too large a capsule is needed to provide the dose.
Nanoparticles, described in U.S. Pat. No. 5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic agent onto which are adsorbed a non-crosslinked surface modifier, and which have an average particle size of less than about 400 nanometers (nm).
The present invention provides improved oral bioavailability for any compound which possesses extensive first pass elimination and that can be formulated as a nanoparticulate in a digestible oil or fatty acid. It is theorized that nanoparticles are rapidly carried intact into the intestinal lymphatic ducts/vessels via the lipid transport pathway where subsequent dissolution in lymph/blood partitioning occurs. Eventually, any undissolved nanoparticulate will drain into the systemic circulation and represent a late phase delivery pathway.